Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide.

Abstract

alpha-Galactosylceramide (alpha-GalCer) is a glycolipid that stimulates natural killer T cells to produce both T helper (Th) 1 and Th2 cytokines. This property enables alpha-GalCer to ameliorate a wide variety of infectious, neoplastic, and autoimmune diseases; however, its effectiveness against any one disease is limited by the opposing activities of the induced Th1 and Th2 cytokines. Here, we report that a synthetic C-glycoside analogue of alpha-GalCer, alpha-C-galactosylceramide (alpha-C-GalCer), acts as natural killer T cell ligand in vivo, and stimulates an enhanced Th1-type response in mice. In two disease models requiring Th1-type responses for control, namely malaria and melanoma metastases, alpha-C-GalCer exhibited a 1,000-fold more potent antimalaria activity and a 100-fold more potent antimetastatic activity than alpha-GalCer. Moreover, alpha-C-GalCer consistently stimulated prolonged production of the Th1 cytokines interferon-gamma and interleukin (IL)-12, and decreased production of the Th2 cytokine IL-4 compared with alpha-GalCer. Finally, alpha-C-GalCer's enhanced therapeutic activity required the presence of IL-12, which was needed to stimulate natural killer cells for optimal interferon-gamma production, but did not affect IL-4. Overall, our results suggest that alpha-C-GalCer may one day be an excellent therapeutic option for diseases resolved by Th1-type responses.

• Authors: John Schmieg, Guangli Yang, Richard W Franck, Moriya Tsuji
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 198 Issue 11 Pg. 1631-41 (Dec 01 2003) ISSN: 0022-1007 [Print] United States
• PMID: 14657217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• Galactosylceramides
• Ligands
• Interferon-gamma

Topics

• Animals
• Base Sequence
• DNA Primers
• Female
• Galactosylceramides (immunology)
• Interferon-gamma (biosynthesis)
• Killer Cells, Natural (immunology, metabolism)
• Ligands
• Malaria (immunology)
• Melanoma, Experimental (pathology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Metastasis (immunology)